The invention relates to new 14,15-cyclopropanosteroids of the 19-norandrostane series, their synthesis and pharmaceutical preparations containing these compounds.
14,15-Cyclopropanosteroids of the 19-norandrostane series of the following formula 
are described in the German application No. 198 27 522.5 (PCT/DE99/01795), which claims a priority earlier than that of the present application, but was published after the latter was filed.
In the above formula, R1 is a hydrogen atom or an alkyl group with 1 to 9 carbon atoms,
R2 represents a hydrogen atoms or a methyl group,
R3 and R4 independently of one another represent a hydrogen atom, a hydroxy group, an acyloxy group xe2x80x94Oxe2x80x94COxe2x80x94R5, in which R5 represents 1 to 10 carbon atoms, a carbamoyloxy group Oxe2x80x94COxe2x80x94NHR6, in which R6 represents a hydrogen atom, an alkyl group or an acyl group in each case with 1 to 5 carbon atoms,
a sulfamoyloxy group xe2x80x94Oxe2x80x94SO2xe2x80x94NR7R8, in which R7 and R8 independently of one another represent a hydrogen atom, an alkyl group with 1 to 5 carbon atoms or, together with the nitrogen atom, represent a pyrrolidino, piperidino or morpholino group,
a xe2x80x94CH2R9 group, in which R9 represents hydroxy group, an alkoxy group, with 1 to 5 carbon atoms, a chlorine or bromine atom, an azide, nitrilo or thiocyano group or a xe2x80x94SR10 group, in which R10 represents an alkyl group with 1 to 5 carbon atoms,
or R3 and R4 together represent an oxo group
or R3 and R4, with inclusion of the C-17, form a spirooxirane group or a 2,2-dimethyl-1,3-dioxolane and the 14,15-cyclopropane ring is either in the xcex1 a or xcex2 position.
The EP 0 768 316 A1 discloses steroids with 14,15-methylene groups, which have progesterone activity and therefore, in combination with at least one suitable estrogen, are suitable for hormonal contraception and menopausal hormone replacement therapy (HRT), as well as for the treatment of endometriosis or gestagen-dependent tumors.
With this state of the art as background, it is an object of the present invention to make available new, unsaturated, 14,15-cycloprano-androstanes.
This objective is accomplished by 14,15-cyclopranoandrostanes of the 19-norandrostane series of the general formula (I) 
in which R1 is a hydrogen atom, a hydroxy group, C1-10-alkyl, C1-10-alkyloxy, C1-15acyloxy, C4-15-aryloxy, C7-15-aralkyloxy or a C7-15-alkylaryloxy group
R2 represents a hydrogen atom, a hydroxy group, a C1-10 alkyl, C1-10 acyl, C1-10 acyloxy, C6-15 aryl, C7-15 aralkyl or C7-15 alkylaryl group
a xe2x80x94(CH2)nCH2Y group
with n=0, 1 or 2 and Y represents a halogen atom, especially a fluorine, chlorine, bromine or iodine atom, a pseudohalogen, especially a cyano, azide or rhodanide group,
xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CH(CH2)pxe2x80x94R6 group
with m=0, 1, 2 or 3 and p=0, 1 or 2 and R5 represents a hydrogen atom, a C1-10 alkyl, C6-15 aryl, C7-15 aralkyl or C7-15 alkylaryl group or a hydroxyl group, a C1-10 alkyloxy group or a C1-10 acyloxy group,
a xe2x80x94(CH2)oC CR7 group
with o=0, 1 or 2 and R6 represents a hydrogen atom, a halogen atom, especially a fluorine, chlorine, bromine or iodine atom, a C1-10 alkyl, C6-15 aryl, C7-15 aralkyl, C7-15 alkylaryl or C1-10 acyl group
R1 and R2 together represent a keto, methylene, difluoromethylene group or, with inclusion of the C-17, a spirooxirane or a 2,2-dimethyl-1,3-dioxolane,
R3 represents a hydrogen atom or an xcex1 or xcex2 C1-10 alkyl group,
R4 represents a halogen atom, especially a fluorine, chlorine or bromine atom, or a pseudohalogen, especially a rhodanide or azide group, or a hydroxyl or perfluoroalkyl group and
R5 represents a C1-4 alkyl group, there being an xcex1- or xcex2-cyclopropane group between C-14 and C-15,
and possibly double bonds in the 9,10 or 11,12 position,
with the proviso that, if there are 2 further double bonds in the 9,10 and 11,12 positions or one double bond in the 11,12 position, R4 can be a hydrogen atom in addition to the meanings given above and with the further proviso that, when R5 is a methyl group, R4 can be a hydrogen atom in addition to the meanings given above, as well as their pharmaceutically tolerated salts.
Surprisingly, the compounds of formula (I) show an interesting mixed androgen/gestagen profile, the androgenic or gestagenic activity predominating depending on the substitution.
Within the sense of the invention, pharmaceutically tolerated salts are alkali or alkaline earth salts, especially sodium, potassium or ammonium salts. These salts can be synthesized by standard techniques and methods, which are well known in the art.
Within the sense of the present invention, a xe2x80x9cC1-4 or C1-10 alkyl groupxe2x80x9d is understood to be a branched or linear alkyl group with 1 to 4 or 1 to 10 carbon atoms. As examples, a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, n-pentyl, i-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl or 2,3-dimethylbutyl group are mentioned.
Within the sense of the present invention, the concept of xe2x80x9cC1-10 alkoxy groupxe2x80x9d is understood to include cyclic or acyclic groups, the alkyl portion of which contains 1 to 10 carbon atoms. xe2x80x9cCyclic groupsxe2x80x9d are understood to include also heterocyclic groups, which may have 1 or 2 hetero atoms in the ring, which may be selected from a nitrogen atom, an oxygen atom and a sulfur atom. A methoxy group, an ethoxy group or an n- or iso-propoxy group or an iso- or t-butoxy, a 1xe2x80x2-methoxy-cyclopentoxy or a tetrahydropyranyloxy group are examples.
In the sense of the present application, the concept of C1-10 or C1-15 acyl or acyloxy groupxe2x80x9d is understood to be a group with 1 to 10 or 1 to 15 carbon atoms of the linear or branched alkane carboxylic acids, such as formic acid, acetic acid, propionic acid, butyric acid, iso-butyric acid, heptanoic acid or undecanoic acid.
Within the sense of the present application, the concept of a xe2x80x9cC6-15 aryl groupxe2x80x9d is understood to include a substituted or unsubstituted aryl group with 6 to 15 carbon atoms, such as a phenyl group, a substituted phenyl group, such as a halogenated phenyl group or a nitrophenyl group, or a naphthyl group.
Within the sense of the present application, the concept of a xe2x80x9cC4-15 aryloxy groupxe2x80x9d is understood to include a carbocyclic or heterocyclic group with 4 to 15 carbon atoms. Examples are a benzoyloxy group, a 1- or 2-naphthinyloxy group, a 2- or 3-furanyloxy group, a 2- or 3-thienyl group and a 2-, 3- or 4-pyridinyloxy group.
Within the sense of the present application, the concept of a xe2x80x9cC7-15 alkylaryl groupxe2x80x9d is understood to include an aryl group, which is substituted by an alkyl group, the two group together of 7 to 15 carbon atoms. The aryl group may have additional substituents, such as a halogen atom. Examples are a toluenyl group (methylphenyl group), a halogenated toluenyl group, an ethylphenyl group, a dimethylphenyl group or a trimethylphenyl group.
Within the sense of the present application, the concept of a xe2x80x9cC7-15 alkylaryloxy groupxe2x80x9d is understood to be a xe2x80x9cC7-15 aralkyl groupxe2x80x9d, such as a 3- or a 4-methylphenyloxy group, which is extended by an oxygen atom.
Within the sense of the present application, the concept of a xe2x80x9cC7-15 aralkyl groupxe2x80x9d is understood to include an alkyl group, which is substituted by an aryl group, the two groups together having 7 to 15 carbon atoms. The aryl group may have further substituents, such as a halogen atom. Examples are a free or an aromatically substituted benzyl groups, such as a benzyl group or a halogenated benzyl group.
Within the sense of the present application, the concept of xe2x80x9cC7-15 aralkyloxy groupxe2x80x9d is understood to include xe2x80x9cC7-15 aralkyl groupsxe2x80x9d, which has been extended by an oxygen atom, such as a benzyloxy group.
Within the sense of the present application, the concept of xe2x80x9chalogenxe2x80x9d comprises a fluorine, bromine or iodine atom.
Within the sense of the present application, the concept of xe2x80x9cpseudohalogenxe2x80x9d comprises a cyanate, rhodanide, cyan or azide group.
Within the sense of the present application, the concept of xe2x80x9cperfluoroalkyl groupxe2x80x9d comprises branched or linear fluoroalkyl groups with 1 to 3 carbon atoms, such as a trifluoromethyl, pentafluoroethyl, heptafluoro-n-propyl or heptafluoro-i-propyl group.
R1 preferably represents a hydroxy or C1-11 acyloxy group, especially a formyloxy, acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy, heptanyloxy or undecanyloxy group.
If R2 represents a xe2x80x94(CH2)nCH2Y group, n preferably is 1 and Y preferably represents a fluorine atom or a cyano or rhodanide group. If R2 is a xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CH(CH2)pxe2x80x94R6 group, n preferably is 1 and R6 preferably represents a methyl or ethyl group or a methoxy or ethoxy group.
If R2 represents a xe2x80x94(CH2)oC CR7 group, o preferably is 1 and R7 preferably represents a fluorine atom or a methyl or ethyl group.
R2 especially represents a hydrogen atom or a C1-6 alkyl group, especially a methyl or ethyl group.
R3 preferably represents a C1-4 alkyl group, a methyl group being especially preferred.
R4 preferably represents a fluorine, chlorine or bromine atom or a trifluoromethyl or hydroxy group, and R5 preferably represents a methyl or ethyl group.
The most preferred compounds are the following
1) 4-chloro-17xcex2-hydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
2) 4-chloro-17xcex1-hydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
3) 4-chloro-17xcex2-hydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3-one
4) 4-chloro-17xcex1-hydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3-one
5) 4-bromo-17xcex2-hydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
6) 4-bromo-17xcex1-hydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
7) 4-bromo-17xcex2-hydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3-one
8) 4-bromo-17xcex1-hydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3 -one
9) 4-fluoro-17xcex2-hydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
10) 4-fluoro-17xcex1-hydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
11) 4-fluoro-17xcex2-hydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3-one
12) 4-fluoro-17xcex1-hydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3-one
13) 4,17xcex2-dihydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
14) 4,17xcex1-dihydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
15) 4,17xcex2-dihydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3-one
16) 4,17xcex1-dihydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3-one
17) 4-trifluoromethyl-17xcex2-hydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
18) 4-trifluoromethyl-17xcex1-hydroxy-14xcex1,15xcex1-methylene-estr-4-ene-3-one
19) 4-trifluoromethyl-17xcex2-hydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3-one
20) 4-trifluoromethyl-17xcex1-hydroxy-14xcex2,15xcex2-methylene-estr-4-ene-3-one
22) 17xcex2-hydroxy-14xcex1,15xcex1-methylene-estra-4,9,11-triene-3-one
23) 17xcex1-hydroxy-14xcex1,15xcex1-methylene-estra-4,9,11-triene-3-one
24) 17xcex2-hydroxy-14xcex1,15xcex1-methylene-estra-4,9,11-triene-3-one
25) 17xcex2-hydroxy-14xcex2,15xcex2-methylene-estra-4,9,11-triene-3-one and
26) 17xcex1-hydroxy-14xcex2,15xcex2-methylene-estra-4,9,11-triene-3-one
The inventive compounds of formula (I) can be synthesized in that, in 14, 15-cyclopropanosteriods of the general formula (II) 
in which R1, R2, R3 and R5 have the meaning given above, the 4, 5 double bond is epoxidized with hydrogen peroxide under alkaline conditions and the resulting epoxide mixture is treated in a suitable solvent with acids having the general formula HR8, R8 being a halogen atom or a pseudohalogen atom, or reacted with catalytic amounts of a mineral acid and the 4-bromo compound of the general formula (I), obtained above, is reacted with methyl 2,2-difluoro-2-(fluorosulfonyl) acetate in dimethylformamide in the presence of CuI.
The synthesis of compounds of formula (II) is carried out by known methods or described in the German application No. 198 27 522.6 (PCT/DE99/01795). In the application referred to, the introduction of the groups, which occur there and are analogous to the R1, R2, R3 and R5 groups claimed here, is described.
Moreover, corresponding 4-bromo compounds can also be synthesized by the addition of bromine by means of bromine, N-bromosuccinimide or N-bromoacetamide to compounds of the general formula (II) in a mixture of acetic acid and ether in the presence of a proton acceptor, such as collidine (X. S. Fei et. al., J. Chem. Soc. Perkin Trans. 1, 1998, 1139-1142).
4-Trifluoromethyl compounds of the general formula (I) can be obtained by reacting the 4-bromo compounds of the general formula (I), obtained above, with methyl 2,2-difluoro-2-(fluorosulfonyl)-acetate in dimethylformamide in the presence of CuI (X. S. Fei et. al., J. Chem. Soc. Perkin Trans. 1, 1998, 1139-1142). 4-Hydroxy compounds are obtained by reacting the epoxide mixture, given above, with catalytic amounts of mineral acid, such as sulfuric acid (P. S. Furth et. al., J. Enzyme Inhibition, 1990, v. 4, 131-135). Compounds of the general formula (I), which contain a 4,9,11-triene structure, can be transformed from compounds of the general formula (III) 
in which R1, R2, R3 and R5 have the meaning given above (synthesized, for example, according to the method of EP 0 768 316 A1) by methods known from the literature into compounds with a 4,9,11-triene structure of the general formula (I). Accordingly, compounds such as those of the general formula (III) can be ketalized in the 3 position, a 5(10),9(11) diene being formed. After careful hydrolysis of the ketal group of, a 5(10),9(11)-diene-3-one is then obtained, which can easily be dehydrogenated with dichlorodicyanobenzoquinone to the desired compounds of the general formula (I) (according to the method of M. Heller, R. H. Lenhard, S. Bernstein, Steroids 1967, pp. 211-217). In addition, it is possible to convert the 5(10),9(11)-diene-3-one into the 11xcex2-hydroperoxide. After the 11xcex2-hydroperoxide is reduced to the 11xcex2-hydroxy compound, the hydroxy group can be split off under acidic conditions with the formation of the desired compounds of the general formula (I) by the method of L. Nedelec, V. Torelli, G. Costerousse, V. Delaroff, Bull. Soc. Chim., 1977, pages 670-675).
Pharmaceutical drugs, for the oral, rectal, subcutaneous, intravenous oral intramuscular application which, together with the conventional vehicles and diluents, contain at least one compound of the general formula (I) and/or their acid addition salts as active ingredient, are also an object of the present invention.
Pharmaceutical preparations of the invention are produced with the usual solid or liquid vehicles and/or diluents and the inactive ingredients usually used in accordance with the desired type of application in a suitable dosage and by known procedures. In the case of a preferred oral form of administration, preferably tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions are prepared also in sustained release form. In addition, parenteral forms of medicinal drugs, such as injection solutions or suspensions, can also be considered.
Medicinal drug forms as tablets can be obtained for example by mixing the active ingredient with the known inert materials, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents, which can achieve a sustained release effect, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of several layers.
Similarly, coated tablets can be prepared by coating cores, prepared similarly to the tablets, with agents used in conventional tablet coatings, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The tablet coating may consist of several layers, the inert materials, named above, for example being used.
To improve the taste, the solutions or suspensions with the inventive active ingredients can be mixed with materials such as saccharin, cyclamate or sugar and/or with aromatic and flavoring materials such as vanillin or orange extract. Moreover, they may be mixed with suspending agents, such as sodium carboxymethylcellulose, or preservatives, such as p-hydroxybenzoic acid.
Capsules can be prepared by mixing medicinal drugs with vehicles, such as lactose or sorbitol, which are then brought into the capsules.
Suppositories are prepared preferably by mixing active ingredients with suitable vehicles, such as neutral fats or polyethylene glycols or their derivatives.
The pharmaceutical forms of preparations furthermore can be percutaneous forms, such as transdermal therapeutic systems (TTS) or gels, sprays or ointments or intranasal forms, such as nose sprays or oral nose drops.
The inventive 14,15-cyclopropanosteroids of the 19-norandrostane series of the general formula (I) are compounds with hormonal (gestagenic and/or androgenic) activity.
For example, 4-chloro-17xcex2-hydroxy-14xcex1,14xcex1-methylene-estr-4-ene-3-one binds to the extent of 98% to the androgen receptor to (R 1881=100%) and to the extent of 5.5% to the progesterone receptor (progesterone=100%). On the other hand, 17xcex2-hydroxy-14xcex1,15xcex1-methylene-estra-4,9,11-triene-3-one binds to the extent of 58% to the androgen receptor and to the extent of 36% to the progesterone receptor. These test results open up various possibilities for the inventive compounds of the general formula (I) for fertility control in men and women, hormone replacement therapy in men and women or the treatment of hormonally induced diseases in men and women, such as endometriosis, breast cancer or hypogonadism.